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Chemopreventive Agents
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
There is also some evidence that individuals with mutations in the SLC22A4 ergothioneine transporter are more prone to autoimmune disorders such as Crohn’s disease and rheumatoid arthritis, and there are data in the literature to suggest that these mutated transporter proteins transport ergothioneine more efficiently than the wild-type proteins. Interestingly, there is also evidence that rheumatoid arthritis is associated with higher blood ergothioneine levels in red blood cells.
Effects of single-nucleotide polymorphism on the pharmacokinetics and pharmacodynamics of metformin
Published in Expert Review of Clinical Pharmacology, 2022
Shaoqian Li, Bo Xu, Shangzhi Fan, Bo Kang, Lijing Deng, Danjun Chen, Bo Yang, Fan Tang, Zunbo He, Yong Xue, Jie-Can Zhou
Carnitine/organic cation transporter 1 (OCTN1) is a poly-specific, bidirectional and pH-dependent organic cation transporter with low carnitine transporter activity [79], which is a remarkably expressed in the kidney, trachea, bone marrow and liver [80]. OCTN1 accepts various types of organic cationic and zwitterionic compounds as substrates [81,82]. Recently, metformin has shown to be a substrate of OCTN1 in a mouse study [30]. Therefore, OCTN1 may be a factor influencing the pharmacokinetics of metformin. Previous studies have found that the Octn1 gene Slc22a4 rs272893 (c.917C>T, T306I) polymorphism evidently affected the pharmacokinetics of metformin [83]. In another pharmacokinetic study of 103 healthy Caucasian men, rs1050152 (c.1507C>T, L503F) in Slc22a4 had no effect on the pharmacokinetics of metformin [44]. Thus, considerable evidence regarding the upshot of OCTN1 polymorphism on the efficacy of metformin is needed.
Circadian clock-controlled drug metabolism and transport
Published in Xenobiotica, 2020
Mengjing Zhao, Huijie Xing, Min Chen, Dong Dong, Baojian Wu
In the study of Wada et al. (2015), soluble carrier protein family 22 member 4 (Slc22a4), an organic cation transporter, exhibited a circadian expression (the protein levels were higher during the dark phase) in mouse intestine. Slc22a4 is involved in the uptake transport of gabapentin (an antiepileptic drug). Oscillations in Slc22a4 expression led to dosing time-dependent intestinal absorption of gabapentin (gabapentin exposure at ZT14 was significantly higher than that at ZT2) (Wada et al., 2015). The authors further proposed that rhythmic Slc22a4 expression is generated in part by time-dependent intestinal accumulation of bile acids that periodically suppress PPARα transactivation of Slc22a4 (Wada et al., 2015).
Recent advances in drug delivery via the organic cation/carnitine transporter 2 (OCTN2/SLC22A5)
Published in Expert Opinion on Therapeutic Targets, 2018
Longfa Kou, Rui Sun, Vadivel Ganapathy, Qing Yao, Ruijie Chen
L-Carnitine (β-hydroxy-γ-trimethylaminobutyrate), also named as vitamin Bt, is a highly polar zwitterionic molecule. It plays an essential role in the transfer of long-chain fatty acids from the cytoplasm into the mitochondrial matrix across the inner mitochondrial membrane for β-oxidation [1], and the transport of peroxisomal β-oxidation metabolites into mitochondria for completion of oxidation via tricarboxylic acid (TCA) cycle [2,3]. L-Carnitine also functions as an effective scavenger of reactive oxygen species (ROS) to prevent oxidant injury [3,4]. The deficiency of L-carnitine in body could result in lipid metabolism disorders, hypoglycemia, skeletal weakness, cardiac hypertrophy, hyperammonemia, and even death [5,6]. L-Carnitine is synthesized de novo to a significant extent in the liver, kidney and brain using lysine as a carbon backbone and methionine as a donor of methyl groups; it is also available in the diet with efficient absorption in the intestinal tract, which is the major contributor to L-carnitine in the body. Intestinal absorption, distribution in systemic tissues, and reabsorption in the kidney of L-carnitine rely principally on the carnitine/organic cation transporter OCTN2, also known as SLC22A5, which shows high affinity for this important metabolite/nutrient with the Michaelis constant in the low micromolar range. There are other transporters that also show ability to transport L-carnitine; these are OCTN1 (SLC22A4), CT2 (SLC22A16), and ATB°,+ (SLC6A14), but the affinity of these transporters for L-carnitine is much lower than that for OCTN2 and also their tissue distribution is different from that of OCTN2 (Table 1) [7].